CN113072582B - Pi-pi conjugated pyridyl lipid derivative and preparation method and application thereof - Google Patents
Pi-pi conjugated pyridyl lipid derivative and preparation method and application thereof Download PDFInfo
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- CN113072582B CN113072582B CN202110378732.4A CN202110378732A CN113072582B CN 113072582 B CN113072582 B CN 113072582B CN 202110378732 A CN202110378732 A CN 202110378732A CN 113072582 B CN113072582 B CN 113072582B
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- pyridyl
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- liposome
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- lipid
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- 238000012546 transfer Methods 0.000 description 1
- 238000004627 transmission electron microscopy Methods 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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Abstract
The invention provides a lipid derivative containing pi-pi conjugated pyridyl and a preparation method and application thereof; the synthesis method of the pi-pi conjugated pyridyl lipid derivative is simple, the cost of raw materials is low, reaction reagents are easy to obtain and have no pollution, and the reaction conditions are mild; the method has better popularization and is beneficial to large-scale production; compared with the traditional liposome preparation, the pi-pi conjugated pyridyl liposome provided by the invention can obviously increase the drug loading capacity of the adriamycin nano liposome by utilizing the pi-pi stacking effect, improve the stability of the preparation, realize the oxidative stimulation release of the drug to tumor tissues and enhance the curative effect; when the adriamycin pyridyl functionalized liposome prepared from the pi-pi conjugated pyridyl lipid derivative is used for in vivo tests, the adriamycin pyridyl functionalized liposome has no toxic or side effect on the kidney and the liver of a mouse, does not influence the normal growth of the mouse, and has high bioavailability.
Description
Technical Field
The invention belongs to the field of biological medicine; in particular to a lipid derivative containing pi-pi conjugated pyridyl and a preparation method and application thereof.
Background
The nano-drug is a drug with the size of 20-200nm formed by encapsulating an anti-tumor drug into a carrier by a certain physical encapsulation or chemical bond connection method. Compared with the traditional micromolecular chemotherapy drugs, the nano-drug has the following advantages: 1) The solubility and the stability of the medicine are improved, and the blood circulation time of the medicine is prolonged; 2) Passively targeting to tumor tissues by utilizing enhanced high-flux and retention Effect (EPR), and enhancing the bioavailability of the drug; 3) Antigen-antibody and receptor-ligand mediated active targeting molecules can be designed, so that high drug uptake and high tumor tissue penetration are realized, toxic and side effects are reduced, and a better treatment effect is obtained; 4) The controllable release of the loaded drug is adjusted by introducing stimulus response (exogenous stimulus and endogenous stimulus), so that the curative effect is further improved. Based on this, the nano-drug can significantly improve the treatment effect of tumor-related diseases.
Liposomes have been widely used as a nano-drug carrier for the delivery of small molecule drugs and nucleic acids, and various liposomal nano-drugs are approved for clinical treatment of tumors, such as doxorubicin liposomes, daunorubicin liposomes, and cytarabine liposomes. However, clinical results show that the therapeutic effect of the nano-drug is still not completely satisfactory, which is mainly due to the inherent problems of low drug loading rate (< 10%), poor stability, insufficient endocytosis capacity to enter tumor cells, slow intracellular release and the like. Therefore, how to make use of the advantages and avoid the hazards, make the best of the advantages and avoid the disadvantages, give play to the toxicity reduction and the synergy of the liposome nano-medicament to the maximum extent, have great significance for the treatment of tumor medicaments and have great clinical application prospects.
Aiming at the problem that the existing liposome nano-drug is difficult to meet the functional challenges of high drug-loading capacity, high stability and intracellular response and release, the invention provides a pi-pi conjugated pyridyl-containing disulfuroacylcholine and application thereof in adriamycin nano-drugs. The stable and efficient loading of the drug is effectively realized by utilizing the strong pi-pi accumulation effect between the pyridine-based lipid material and the adriamycin drug molecules, but the drug can be subjected to redox degradation in a tumor microenvironment to quickly release the wrapped drug, so that the drug effect is improved. The dithiopyridyl lipid derivative and the adriamycin liposome prepared from the same have the characteristics of high drug loading capacity and high stability, solve the problems of low drug loading and potential safety hazard of the adriamycin liposome clinically applied at present to a certain extent, and have important significance for developing functional carrier materials with independent intellectual property rights in China.
Disclosure of Invention
The invention aims to provide a lipid derivative containing pi-pi conjugated pyridyl and a preparation method and application thereof.
The invention is realized by the following technical scheme:
in a first aspect, the present invention relates to a pi-pi conjugated pyridyl lipid derivative represented by the general chemical structural formula (I):
wherein the content of the first and second substances,
n is an integer of 5 to 8;
the pi-pi conjugated lipid derivative takes a biocompatible pyridyl group as a hydrophobic part of a lipid molecule, provides a pi-pi stacking effect, and is combined with a small molecule hydrophobic drug of an aromatic structure through non-covalent bonds to enhance the stability and drug loading capacity in the drug delivery process.
In a second aspect, the invention also relates to a method for synthesizing the pi-pi conjugated pyridyl lipid derivative, which comprises the following steps:
the invention provides a synthetic method of the lipid derivative containing pi-pi conjugated pyridyl. The synthesis method is efficient, rapid, good in universality, high in yield, low in synthesis cost, environment-friendly in synthesis process and suitable for industrial scale-up production.
The invention also provides the application of the pi-pi conjugated pyridyl lipid derivative in the technical scheme in the preparation of the functionalized blank liposome and the application of the functional blank liposome in a drug carrier.
In a third aspect, the functionalized blank liposome prepared from the pi-pi conjugated pyridyl lipid derivative provided by the invention has an average particle size of 120-300nm, is spherical and uniform in size;
the common phospholipid comprises one or more of lecithin, soybean phospholipid, egg yolk lecithin, hydrogenated soybean lecithin, distearoyl phosphatidylcholine, distearoyl phosphatidylglycerol, dipalmitoyl lecithin, etc.;
preferably soybean lecithin, egg yolk lecithin and hydrogenated soybean lecithin;
the molar ratio of the phospholipid, cholesterol and DSPE-PEG2000 is 50-60;
the blank liposome has the hydration temperature of 50-60 ℃ and the hydration time of 1-3h;
in a fourth aspect, the invention also provides a preparation method of the adriamycin drug-loading functionalized liposome, wherein the adriamycin drug-loading functionalized liposome is prepared by an ammonium sulfate gradient method.
The preparation method of the adriamycin pyridyl functionalized liposome comprises the following steps:
1) Preparing blank liposome: dissolving disulfide pi-pi conjugated pyridyl phospholipid, soybean lecithin, cholesterol and DSPE-PEG2000 in chloroform/methanol (volume ratio v/v = 4:1) according to a certain molar ratio, rotating at 40-50 ℃ to form a film, and hydrating with 100-300mmol/L ammonium sulfate for 1-3h;
2) Preparing the ammonium sulfate gradient blank liposome by a dialysis method: putting the blank liposome liquid obtained in the step 1) into a dialysis bag (molecular weight cut-off 3500D), and dialyzing for 4-6h by using phosphate buffer solution (PBS, pH = 7.4) as a dialysis medium; the liposome vesicles sequentially pass through polycarbonate membranes with the diameters of 800nm, 450nm and 220nm to finally form the ammonium sulfate gradient blank liposome;
3) Mixing the ammonium sulfate gradient blank liposome in the step 2) with adriamycin aqueous solution, and incubating for 40min at 40-50 ℃ to obtain the adriamycin pyridyl functionalized liposome.
Wherein, the mass ratio of the adriamycin to the phospholipid is 1:5-1, preferably 1:8-1;
the adriamycin medicine pyridyl liposome provided by the invention has the average particle size of 150-300nm, is spherical and has uniform size;
in a fifth aspect, the present invention provides the use of the above doxorubicin liposome in tumor treatment; the tumor includes leukemia (lymphocytic and granulocytic), malignant lymphoma, breast cancer, bronchogenic carcinoma (undifferentiated small cell and non-small cell), ovarian cancer, soft tissue sarcoma, osteogenic sarcoma, rhabdomyosarcoma, ewing's sarcoma, blastoma, neuroblastoma, bladder cancer, thyroid cancer, prostate cancer, head and neck squamous cell carcinoma, testicular cancer, gastric cancer, or liver cancer.
The invention has the following advantages:
1) The synthesis method of the pi-pi conjugated pyridyl lipid derivative is simple, the cost of raw materials is low, reaction reagents are easy to obtain and have no pollution, and the reaction conditions are mild; the method has better popularization and is beneficial to large-scale production;
2) Compared with the traditional liposome preparation, the pi-pi conjugated pyridyl liposome provided by the invention can obviously increase the drug-loading rate of the adriamycin nano liposome by utilizing the pi-pi stacking effect, improve the stability of the preparation, realize the oxidative stimulation release of the drug to tumor tissues and enhance the curative effect;
3) When the adriamycin pyridyl functionalized liposome prepared from the pi-pi conjugated pyridyl lipid derivative is used for in vivo tests, the adriamycin pyridyl functionalized liposome has no toxic or side effect on the kidney and liver of a mouse, does not influence the normal growth of the mouse, and has high bioavailability;
4) The novel pi-pi conjugated pyridyl lipid derivative with high drug loading capacity and high stability provided by the invention can become a novel carrier platform for clinical chemotherapy treatment.
Drawings
Figure 1 is the results of the pharmaceutical characterization of the blank pyridyl liposomes of the present invention: a) A particle size distribution map; b) A transmission electron microscope image;
FIG. 2 is a graph showing the in vitro release results of the pyridyl liposome of doxorubicin of the present invention;
FIG. 3 is a graph of the effect of doxorubicin pyridyl liposomes of the invention on MCF-7 cell survival;
FIG. 4 is a graph of the effect of doxorubicin pyridyl liposomes of the invention on A549 cell survival;
FIG. 5 is a graph of the effect of doxorubicin pyridyl liposomes of the present invention on HepG-2 cell survival;
FIG. 6 is a graph showing the in vivo tumor growth of the nude mice bearing MCF-7 tumor with the doxorubicin preparation of the present invention
FIG. 7 is a graph of the in vivo body weight changes of the doxorubicin preparation of the present invention against MCF-7 tumor-bearing nude mice.
FIG. 8 is a reaction scheme of a method for synthesizing a π - π conjugated pyridyl lipid derivative according to the present invention.
Detailed Description
The present invention will be described in detail with reference to specific examples. It should be noted that the following examples are only illustrative of the present invention, but the scope of the present invention is not limited to the following examples.
Example 1
The synthesis of triphenyl ether protected mercaptoundecanoic acid has the following chemical structural formula:
1g/4.58mmol of mercaptoundecanoic acid is dissolved in 20mL of anhydrous dichloromethane, and a solution of 2.55g/9.16mmol of triphenylchloromethane in dichloromethane is added dropwise with stirring and reacted at room temperature for 6h. After the completion of the reaction, the reaction mixture was concentrated and recrystallized 2 times from 200mL of petroleum ether to obtain 2.01g of a white solid with a yield of 95.2%.
1 H NMR(500MHz,CDCl 3 ):δ7.36–7.23(m,9H),2.59(s,1H),2.27(s,1H),1.63(s,1H),1.47(s,1H),1.40(d,J＝7.7Hz,2H),1.31(dd,J＝18.0,5.5Hz,5H)； 13 C NMR(125MHz,CDCl 3 ):δ177.13(s,1H),145.34(s,7H),129.38(s,14H),129.13(s,15H),127.79(s,3H),64.64(s,2H),34.64(s,2H),30.23(s,5H),28.95(t,J＝1.6Hz,15H),24.81(s,2H).HRMS,ESI + ,m/z:Calcd for C 30 H 36 O 2 S[M-H] - :459.24；found 459.24.
Example 2
The synthesis of glyceryl phosphatidyl choline undecanoate protected by bis-triphenyl ether has the following chemical structural formula:
0.46g/0.99mmol of triphenylether-protected mercaptoundecanoic acid and 0.24g/1.49mmol of CDI were dissolved in 15mL of anhydrous dimethyl sulfoxide and activated at 35 ℃ for 2h. To the above reaction system, 0.10g/0.39mmol of glycerophosphorylcholine and 0.23g/1.49mmol of DBU were further added, and the reaction was carried out overnight at 45 ℃. After the reaction was completed, the reaction solution was precipitated with an ether solution containing 10% glacial acetic acid, and after concentration, column chromatography was performed using chloroform/methanol/water (v/v/v =65: 56.4 percent.
1 H NMR(500MHz,CDCl 3 ):δ7.40–7.34(m,14H),7.34–7.25(m,16H),5.43(s,1H),4.51(s,1H),4.29(d,J＝8.0Hz,3H),3.99(d,J＝30.1Hz,2H),3.80(s,2H),3.24(s,9H),2.52(s,2H),2.47–2.38(m,6H),1.74(s,1H),1.73–1.64(m,6H),1.49–1.41(m,6H),1.41–1.13(m,35H). 13 C NMR(125MHz,CDCl 3 ):δ174.55(s,1H),174.36(s,2H),145.34(s,14H),129.38(s,28H),129.13(s,29H),127.79(s,14H),69.29(s,2H),68.20(s,2H),66.81(s,2H),64.64(s,5H),64.25(s,2H),60.53(s,1H),54.72(s,5H),34.09(d,J＝15.0Hz,4H),30.23(s,10H),29.07–28.74(m,47H),25.33(s,5H).HRMS,ESI + ,m/z:Calcd for C 68 H 88 NO 8 PS 2 [M+H] + :1142.57；found 1142.57.
Example 3
The synthesis of dimercaptoundecyl-glycerophosphatidylcholine has the following chemical structural formula:
dissolving 0.2g/0.17mmol of bis-triphenyl ether protected mercaptoalkanoic acid glycerol phosphatidylcholine in 10mL of trifluoroacetic acid/dichloromethane (v/v = 1:1) solution, and reacting at room temperature for 4h; removing trifluoroacetic acid deprotection reagent by rotary evaporation at 50 ℃; to the above system, 0.15g of a 0.68mmol disulfide bipyridine in methylene chloride (10 mL) was added, and the reaction was continued at room temperature for 24 hours; after the reaction was completed, concentration was performed, and column chromatography was performed using chloroform/methanol/water (v/v/v =65: 86.3 percent.
1 H NMR(500MHz,CDCl 3 ):δ8.26(dd,J＝7.5,1.4Hz,3H),7.57–7.52(m,3H),7.35(dd,J＝7.5,1.4Hz,3H),7.20–7.15(m,3H),5.45(s,1H),4.63–4.42(m,2H),4.42–4.38(m,1H),4.33(s,4H),4.01–3.97(m,1H),3.80(s,3H),3.24(s,12H),2.56–2.52(m,5H),2.50(s,3H),2.42(s,3H),1.69(d,J＝5.9Hz,5H),1.63–1.60(m,4H),1.54(dd,J＝47.8,3.9Hz,2H),1.60–1.16(m,34H). 13 C NMR(125MHz,CDCl 3 ):δ174.55(s,2H),174.36(s,1H),160.01(s,3H),145.72(s,3H),139.66(s,3H),121.37(s,3H),119.67(s,1H),69.29(s,1H),68.20(s,1H),66.81(s,1H),64.25(s,1H),60.53(s,1H),54.72(s,5H),38.03(s,3H),34.09(d,J＝15.0Hz,3H),28.93(dd,J＝6.7,5.0Hz,19H),25.33(s,1H).HRMS,ESI + ,m/z:Calcd for C 40 H 66 N 3 O 8 PS 2 [M+H] + :876.35；found 876.35.
Example 4
The synthesis of triphenyl ether protected mercapto hexadecanoic acid has the following chemical structural formula:
1g/3.47mmol of mercaptoundecanoic acid is dissolved in 20mL of anhydrous toluene, and 1.45g/5.19mmol of triphenylchloromethane in toluene is added dropwise while stirring, and the reaction is carried out at room temperature for 6h. After completion of the reaction, the reaction mixture was concentrated and recrystallized 2 times from 200mL of petroleum ether to obtain 1.67g of a white solid with a yield of 93.1%.
1 H NMR(500MHz,CDCl 3 ):δ7.37–7.26(m,7H),7.22–7.18(m,2H),2.54(s,1H),2.28(s,1H),1.65(d,J＝17.9Hz,2H),1.46(s,1H),1.43–1.30(m,10H). 13 C NMR(125MHz,CDCl 3 ):δ177.13(s,1H),145.34(s,7H),129.38(s,14H),129.13(s,15H),127.79(s,7H),64.64(s,2H),34.64(s,2H),30.23(s,5H),29.07–28.74(m,24H),24.81(s,2H).HRMS,ESI + ,m/z:Calcd for C 34 H 44 O 2 S[M-H] - :515.34；found 515.34.
Example 5
The synthesis of hexadecanoic acid glycerol phosphatidylcholine protected by bis-triphenyl ether has the following chemical structural formula:
0.52/1.0mmol of triphenylether-protected mercaptohexadecanoic acid and 0.24g/1.5mmol of CDI were dissolved in 15mL of anhydrous dimethyl sulfoxide and activated at 35 ℃ for 2h. To the above reaction system, 0.10g/0.40mmol of glycerophosphorylcholine and 0.24g/1.5mmol of DBU were further added, and the reaction was carried out overnight at 45 ℃. After the reaction was completed, the reaction solution was precipitated with an ether solution containing 10% glacial acetic acid, and after concentration, column chromatography was performed using chloroform/methanol/water (v/v/v =65 25) to obtain 0.67g of bistriphenyl ether protected mercaptoalkanoic acid glycerol phosphatidylcholine, yield: and (4) 53.8%.
1 H NMR(500MHz,CDCl 3 ):δ7.40–7.34(m,14H),7.34–7.25(m,16H),5.43(s,1H),4.51(s,1H),4.29(d,J＝8.0Hz,3H),3.99(d,J＝30.1Hz,2H),3.80(s,2H),3.24(s,9H),2.52(s,2H),2.47–2.38(m,6H),1.74(s,1H),1.73–1.64(m,6H),1.49–1.41(m,6H),1.41–1.13(m,35H). 13 C NMR(125MHz,CDCl 3 ):δ174.55(s,1H),174.36(s,2H),145.34(s,14H),129.38(s,28H),129.13(s,29H),127.79(s,14H),69.29(s,2H),68.20(s,2H),66.81(s,2H),64.64(s,5H),64.25(s,2H),60.53(s,1H),54.72(s,5H),34.09(d,J＝15.0Hz,4H),30.23(s,10H),29.07–28.74(m,47H),25.33(s,5H).HRMS,ESI + ,m/z:Calcd for C 76 H 104 NO 8 PS 2 [M+H] + :1254.69；found 1254.69.
Example 6
The synthesis of dimercaptohexadecyridyl glycerol phosphatidylcholine has the following chemical structural formula:
0.2g/0.16mmol of bistriphenyl ether protected mercaptoalkanoic acid glycerol phosphatidylcholine was dissolved in 10mL of trifluoroacetic acid/dichloromethane (v/v = 1:1) and reacted at room temperature for 4h. The trifluoroacetic acid deprotection reagent was removed by rotary evaporation at 50 ℃ without further work-up. To the above system, a solution of dithiodipyridine (0.15 g/0.68 mmol) in methanol (10 mL) was added, and the reaction was continued at room temperature for 24 hours. After the reaction was completed, concentration was performed, and column chromatography was performed using chloroform/methanol/water (v/v/v =65: 91.3 percent.
1 H NMR(500MHz,CDCl 3 ):δ8.33–8.19(m,3H),7.58–7.53(m,2H),7.45–7.31(m,3H),7.23–7.18(m,2H),5.36(s,1H),4.74(s,1H),4.35(s,1H),4.27(s,2H),3.94(d,J＝0.8Hz,2H),3.80(s,2H),3.24(s,11H),2.64–2.60(m,5H),2.50(s,3H),2.46(s,2H),1.72(d,J＝13.9Hz,5H),1.65–1.56(m,5H),1.50–1.45(m,5H),1.42–1.28(m,45H). 13 C NMR(125MHz,CDCl 3 ):δ174.55(s,2H),174.36(s,1H),160.01(s,1H),145.72(s,3H),139.66(s,3H),121.37(s,3H),119.67(s,3H),69.29(s,1H),68.20(s,1H),66.81(s,1H),64.25(s,1H),60.53(s,1H),54.72(s,5H),38.03(s,3H),34.09(d,J＝15.0Hz,3H),28.93(dd,J＝6.7,5.0Hz,30H),25.33(s,1H).HRMS,ESI + ,m/z:Calcd for C 48 H 82 N 3 O 8 PS 4 [M+H] + :988.47；found 988.47.
Example 7
Preparation and characterization of blank pyridyl functionalized liposome
The blank pyridyl functionalized liposome is prepared by a film dispersion method. The dithio pi-pi conjugated pyridylphospholipid of example 1 was weighed at a molar ratio of 56 2 Uniformly dispersing in the atmosphere to form a film, and drying in vacuum at 35 ℃ for 10-14h. Carrying out lipid hydration with deionized water or phosphate buffer (pH = 7.4) at 50-60 deg.C for 1-3h. Ultrasonic treatment and filtration with 0.22 μm microporous membrane to obtain pi-pi copolymer with concentration of 1.5-4mg/mLThe yoke pyridyl functionalized liposome is stored at 4 ℃ for standby;
after 1mL of the above blank pyridyl liposome suspension was diluted 20-fold with physiological saline (pH = 7.4), the particle size and particle size distribution thereof were measured by a laser particle size analyzer (DLS), and as shown in fig. 1a, the average particle size of the blank pyridyl liposome was 165 ± 13nm.
10 mu L of liposome suspension diluted by 20 times is taken and dripped on a copper net supported by a carbon film with 300 meshes, and 2 percent of phosphotungstic acid is dyed for 5min. After drying at room temperature, the nano-morphology of the liposomes was observed using Transmission Electron Microscopy (TEM), as shown in fig. 1b, the liposomes were spherical and uniform in size.
Example 8
Preparation and characterization of adriamycin pyridyl functionalized liposome.
The adriamycin pyridyl functionalized liposome is prepared by an ammonium sulfate gradient method. The dithio-pi-conjugated pyridyl phospholipid of example 1 was weighed at a molar ratio of 56 2 Uniformly dispersing in the atmosphere to form a film, and drying in vacuum at 35 ℃ for 10-14h. Hydrating with 100-300mmol/L ammonium sulfate for 1-3 hr;
further, the blank liposome fluid was placed in a dialysis bag (molecular weight cut-off 3500D) and dialyzed for 4-6h using phosphate buffered saline (PBS, pH = 7.4) as a dialysis medium. The liposome vesicle sequentially passes through polycarbonate membranes with the diameters of 800nm, 450nm and 220nm to form the ammonium sulfate gradient blank liposome. And finally, mixing the ammonium sulfate gradient blank liposome with an adriamycin aqueous solution, wherein the mass ratio of adriamycin to phospholipid is 1.
The traditional adriamycin liposome is used as a control group, and the preparation method is the same as the above except that the traditional lecithin is used for replacing the disulfide pi-pi conjugated pyridyl phospholipid. The particle size and potential of the two types of liposomes are shown in Table 1:
TABLE 1
Example 9
Doxorubicin encapsulation efficiency and drug loading rate measurement
Precisely transferring 1mL of adriamycin solution, freeze-drying, and fully dissolving with chromatographic grade methanol. The content of doxorubicin in the sample was measured by ultraviolet-visible spectrophotometry (UV/Vis). The corresponding drug loading (% DLC) and encapsulation efficiency (% DLE) were calculated in combination with the known free drug doxorubicin/water standard curve. The formula is as follows:
encapsulation efficiency (DLE%) = W General assembly -W Swimming device /W General assembly ×100％
Wherein, W General assembly Denotes the total drug content, W Swimming device Indicates the amount of free drug
Drug loading (DLC%) = W General assembly -W Swimming device /Wc×100％
Wherein Wc is the amount of mixed lipid
The encapsulation efficiency of the different modified liposomes is shown in table 2 below:
TABLE 2
As shown in Table 2 above, the encapsulation efficiency gradually increased with the decrease in the drug-to-lipid ratio. Compared with the traditional liposome, the pyridyl liposome has stronger pi-pi stacking effect with adriamycin in the same drug-lipid ratio of 1.
Example 10
In vitro response Release assay
The in vitro response release rate of the adriamycin pyridyl functionalized liposome is determined by a dialysis method. 1.0mL of doxorubicin pyridyl liposome was transferred to a cellulose ester dialysis bag (MWCO 3500 Da) and dialyzed against 20mL of a dialysate containing different concentrations of 0.5mM or 1mM of GSH at 37 ℃. At predetermined time points, 2mL of release medium was sampled and an equal volume of fresh PBS dialysate was added and HPLC was used to determine the concentration of drug released at different time points. The formula for calculating the release rate (%) is: release rate (%) = (Wn/W) × 100%. Wherein Wn is the accumulated release amount of the liposome at a certain time point; w is the total amount of liposome-encapsulated doxorubicin.
As shown in figure 2, in the dialyzates containing different concentrations of 0.5mM or 1mM GSH, the adriamycin pyridyl liposome shows high release rate, the cumulative release amount of adriamycin within 12h reaches 85%, and the adriamycin pyridyl liposome has obvious redox responsiveness.
Example 11
Cytotoxicity assays
1) Cell culture
The breast cancer cell MCF-7, the lung cancer cell A549 and the liver cancer cell HepG-2 are purchased from cell banks of national academy of sciences in Shanghai. The frozen cells were taken and rapidly thawed in a 37 ℃ water bath. Adding the same volume of RPMI-1640 medium containing 10% fetal calf serum, beating, dispersing, centrifuging at 1500rpm for 5min, and discarding the upper layer of frozen stock solution. Continued addition of 1mL of medium and transfer to cell culture flasks at 5% CO 2 And incubating at constant temperature of 37 ℃. After the cultured cells grow to 80% confluence, they are digested with trypsin-EDTA digest, passaged or subjected to the next experiment.
2) MTT assay
Taking MCF-7 or A549 or HepG-2 cells in logarithmic phase according to the proportion of 1 × 10 cells per well 4 By cell density in 96-well plates, 37 ℃, 5% 2 The incubation was carried out overnight. 200 μ L of doxorubicin pyridyl liposomes of different concentrations were added to the experimental group and 200 μ L of blank medium was added to the control group. Each experimental group was set with 6 test concentrations and 6 replicate wells per test concentration. Incubation was continued for 24h after dosing, and pre-formulated MTT solution (20. Mu.L, 5 mg/mL) was added to each well in the dark for 4h incubation. Then, the upper layer of culture medium is discarded, 150. Mu.L of biological grade DMSO is added into each well, and the absorbance value at 570nm is detected by a microplate reader. Cytotoxicity viability was determined as the percentage of absorbance value per well after loading to that of control.
As shown in FIG. 3 (MCF-7 cells), FIG. 4 (A549 cells) and FIG. 5 (HepG-2 cells), the toxicity of doxorubicin pyridyl liposomes was consistent for three tumor cells, with cytotoxicity increasing with increasing drug-loaded liposome concentration. Compared with free adriamycin medicine, the pyridyl liposome has stronger effect of killing cells and has good application prospect in the field of medicine delivery.
Example 12
In vivo pharmacodynamic experiment
1) Establishment of MCF-7 nude mouse xenograft tumor model
Female Balb/c nude mice, 5 weeks old, 16-18g weight, supplied by Jinan Pengyue laboratory animals Inc. Collecting cultured human breast cancer MCF-7 cell suspension at a concentration of 1 × 10 7 g/mL, 0.1mL each was inoculated subcutaneously in the right axilla of nude mice.
2) Pharmacodynamic experiment
After 14 days of inoculation, the tumor grows to 100-150mm 3 Animals were randomly assigned to saline negative control group, free doxorubicin and doxorubicin pyridyl liposome administration group. The injection is administered by tail vein injection, and the administration dose is 5mg/kg, and the injection is performed once every two days. The antitumor effect of the test sample is dynamically observed by using a method of measuring the width (W) and the length (L) of the tumor by using a vernier caliper.
Evaluation of in vivo pharmacodynamics:
1) Tumor volume growth curve: before administration, measuring the growth width (W) and length (L) of the tumor of each test group, calculating the tumor volume according to the following formula, and drawing the change trend of the tumor volume along with the administration time to obtain the growth curve of the tumor volume:
tumor volume = (L × W) 2 )/2
2) Tumor growth inhibition rate: after 24 days of administration, nude mice were sacrificed, tumor masses were surgically removed, weighed and photographed, and the tumor growth inhibition rate was calculated according to the following formula:
tumor growth inhibition rate = (average tumor weight in administration group-average tumor weight in model group)/average tumor weight in model group × 100 (formula VI)
3) In vivo toxicity evaluation:
weight change of nude mice: before administration, the weight of each test group of nude mice was weighed, and the change curve of the weight with the administration time was plotted to evaluate the in vivo safety of the administered nano-drug.
As shown in FIG. 6, compared with the normal saline control group, the traditional doxorubicin liposome and doxorubicin pyridyl liposome can greatly inhibit the increase of tumor volume, and the in vivo tumor inhibition result of the pyridyl liposome (tumor inhibition index 78.9 +/-3.65%) is better than that of the traditional liposome (59.0 +/-4.32%), which is consistent with the in vitro cell experiment and shows that the oxidation responsiveness plays an important role.
As shown in FIG. 7, the body weight change curve of the mice shows that the free adriamycin experimental group has the slowest body weight increase and obvious toxic and side effects; the change curve of the body weight of the mice in the pyridyl adriamycin liposome group is similar to that of the normal saline group, so that the nano administration has the effect of reducing toxic and side effects in vivo.
The derivative synthesized for the first time has good safety, is a redox type pyridyl lipid derivative, and can be used in adriamycin nano-drugs; according to the invention, based on the complex aromatic ring structure of the micromolecular drug, the liposome nano-preparation containing pyridyl dithioglycerol phosphatidylcholine as a drug carrier is designed, and the adriamycin drug is prepared into the liposome nano-preparation which is stable, high in drug loading capacity and redox-responsive, so that the nano-preparation is prevented from being removed by an endothelial reticulum system (RES) in vivo, and thus, the blood circulation is prolonged, and the treatment effect is improved.
The structure of the newly synthesized drug carrier pyridyl functionalized phospholipid is shown as follows:
moreover, the redox-responsive phospholipid prepared by the invention undergoes the following degradation reaction under the action of high-concentration GSH:
because the redox response type pyridyl phospholipid derivative has balanced amphipathy, the derivative can be self-assembled with cholesterol and DSPE-PEG2000 into nano liposome through hydrophilic-hydrophobic and pi-pi accumulation effects to realize efficient package of an adriamycin medicament; when the liposome is targeted to a tumor oxygen microenvironment, the phospholipid disulfide structure is broken in response in GSH high-expression tumor cells, and the liposome nanostructure is destroyed, so that the adriamycin medicine is released in response.
The foregoing description of specific embodiments of the present invention has been presented. It is to be understood that the present invention is not limited to the specific embodiments described above, and that various changes or modifications may be made by one skilled in the art within the scope of the appended claims without departing from the spirit of the invention.
Claims (10)
1. A pi-pi conjugated pyridyl lipid derivative having the following structure:
2. a method for synthesizing lipid derivatives containing pi-pi conjugated pyridyl group according to claim 1, comprising the steps of:
step 1, dissolving mercaptoalkanoic acid in a reaction solvent, dropwise adding a dichloromethane solution of a protective reagent under stirring, wherein the reaction feeding molar ratio of the protective reagent to the mercaptoalkanoic acid is 1:1-1:5, and reacting at room temperature for 4-12 h; after the reaction is finished, performing rotary evaporation to remove dichloromethane, concentrating, and performing recrystallization and purification to obtain triphenylether-protected mercaptoalkanoic acid;
step 2, dissolving triphenylether-protected mercaptoalkanoic acid in a reaction solvent, adding a coupling reagent under stirring, wherein the feeding molar ratio of the triphenylether-protected mercaptoalkanoic acid to the coupling reagent is 1:1-1, 2.5, and performing an activation reaction at 35-45 ℃ for 2-4 h; adding glycerophosphorylcholine and a catalyst to react for 12-14h; the reaction solution is settled by ether solution containing 10 percent glacial acetic acid, and after concentration, chloroform/methanol/water volume ratio of elution solvent is as follows: v/v/v =65, and carrying out column chromatography by using a 4-component column to obtain the bis-triphenyl ether protected mercaptoalkanoic acid glycerol phosphatidylcholine;
step 3, dissolving the bis-triphenyl ether protected mercaptoalkanoic acid glycerol phosphatidylcholine in a deprotection reagent, wherein the deprotection time is 1.5-3h; removing deprotection reagent by rotary evaporation at 50 deg.C; dissolving the obtained deprotected dimercapto long carbon chain phosphatidylcholine in a reaction solvent, adding dithiodipyridine while stirring, wherein the molar ratio of the deprotected dimercapto long carbon chain phosphatidylcholine to the dithiodipyridine is 1.5-1:6, heating to 35-45 ℃, and reacting for 24-48h; after the reaction is finished, concentrating, and then using an elution solvent, wherein the chloroform/methanol/water volume ratio is as follows: v/v/v =65 column chromatography of 4.
3. The method for synthesizing lipid derivatives containing pi-pi conjugated pyridyl group according to claim 2, wherein in the step 1, the protective reagent is triphenylchloromethane; the mercaptoalkanoic acid is mercaptoundecanoic acid, mercaptododecanoic acid or mercaptohexadecanoic acid; the reaction solvent is dichloromethane, toluene, chloroform or dimethylformamide; the recrystallization solvent in the recrystallization purification is ethyl acetate, acetonitrile or petroleum ether.
4. The method for synthesizing lipid derivatives according to claim 2, wherein the reaction solvent in step 2 is dimethyl sulfoxide, dichloromethane or a mixture of dimethyl sulfoxide and dichloromethane; the coupling reagent is N, N' -carbonyldiimidazole or 1,8-diazabicyclo [5.4.0] undec-7-ene; silica gel column chromatography to give white waxy solid bis-thiol protected long carbon chain phosphatidylcholine, the eluting solvent being a mixture of chloroform, methanol, water in a volume ratio of 65.
5. The method for synthesizing lipid derivatives containing pi-pi conjugated pyridyl group according to claim 2, wherein in the step 3, the deprotection reagent is trifluoroacetic acid, and the volume ratio of methyl chloride solution is 1:1 mixture; the molar ratio of the deprotection reagent to the double-mercapto protected long-carbon-chain phosphatidylcholine is 5:1-10, and the reaction is carried out at 50 ℃; the reaction solvent is dichloromethane, methanol, trichloromethane or dimethylformamide; purifying by silica gel column chromatography to obtain a white waxy solid, wherein the elution solvent is a mixture of chloroform, methanol and water in a volume ratio of 65.
6. A blank functionalized liposome prepared from the lipid derivative containing pi-pi conjugated pyridyl group of claim 1, wherein the liposome has an average particle size of 120-300nm, is spherical and uniform in size.
7. The method of preparing blank functionalized liposomes containing pi-pi conjugated pyridyl lipid derivatives as claimed in claim 6, wherein said method comprises the steps of:
1) Dissolving a pi-pi conjugated pyridyl lipid derivative and a co-phospholipid according to a certain molar ratio in a solution of chloroform and methanol according to a volume ratio of 4:1, wherein the concentration of the pi-pi conjugated pyridyl lipid derivative is 1.5-4mg/mL, and the molar ratio of the pi-pi conjugated pyridyl lipid derivative to soybean lecithin, cholesterol and DSPE-PEG2000 is 50-60;
2) Lipid solution in N 2 Uniformly dispersing in atmosphere to form a film, and vacuum drying at 35 ℃ for 10-14 h;
3) Using deionized water or phosphate buffer solution to carry out lipid hydration, and hydrating at 50-60 ℃ for 1-3h; performing ultrasonic treatment and filtering with 0.22 μm microporous membrane to obtain 1.5-4mg/mL pi-pi conjugated pyridyl functionalized liposome, and storing at 4 deg.C.
8. A method of preparing doxorubicin pyridyl-functionalized liposomes from blank functionalized liposomes containing π - π conjugated pyridyl lipid derivatives as described in claim 6, said method comprising the steps of:
1) Preparing blank liposome: dissolving a pi-pi conjugated pyridyl lipid derivative and a co-phospholipid according to a certain molar ratio in a solution of chloroform and methanol according to a volume ratio of 4:1, and rotating at 40-50 ℃ to form a film; hydrating 1-3h with 100-300mmol/L ammonium sulfate;
2) Preparing the ammonium sulfate gradient blank liposome by a dialysis method: putting the blank liposome liquid into a dialysis bag, and dialyzing by using a phosphate buffer solution as a dialysis medium for 4-6h; the liposome vesicles sequentially pass through polycarbonate membranes with the diameters of 800nm, 450nm and 220nm to finally form ammonium sulfate gradient blank liposomes;
3) Mixing the ammonium sulfate gradient blank liposome with adriamycin aqueous solution according to the mass ratio of 1:5-1.
9. Use of a doxorubicin pyridyl-functionalized liposome according to claim 8 for the preparation of a medicament for the treatment of a tumor.
10. Use of an doxorubicin pyridyl-functionalized liposome according to claim 9 in the preparation of a medicament for the treatment of a tumor comprising leukemia, malignant lymphoma, breast cancer, bronchopulmonary carcinoma, ovarian cancer, soft tissue sarcoma, osteogenic sarcoma, rhabdomyosarcoma, ewing's sarcoma, blastoma, neuroblastoma, bladder cancer, thyroid cancer, prostate cancer, head and neck squamous carcinoma, testicular cancer, gastric cancer or liver cancer.
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